This is a NIDA CEBRA R21 application to determine if the deleterious effects of organophosphates on neurodevelopment are due to inhibition of endocannabinoid degradation. Organophosphates are effective and widely used pesticides that have improved human health and crop yields. However, one concerning chronic toxicity of organophosphates is their deleterious effect on neurodevelopment, which can occur independent of acetylcholinesterase (AChE) inhibition. In addition to AChE, organophosphates inhibit other esterases, including fatty acid amino hydrolase (FAAH) and monoacylglycerol lipase (MGL). FAAH and MGL are the two most important enzymes for the degradation of endocannabinoids. Significantly, inhibition of FAAH and MGL occurs at organophosphate concentrations that can be achieved in vivo. How might organophosphates perturb neurodevelopment? Emerging evidence has established that the endocannabinoid system plays a central role in brain development including in the proliferation of neural progenitors, neuronal migration and neural circuit formation. We have found that pharmacological blockade of endocannabinoid signaling and degradation disrupts these processes. In the proposed work we will complete two specific aims to determine if organophosphate inhibition of endocannabinoid degradation leads to abnormalities in neurodevelopment and later behavior: Aim 1. Does perinatal organophosphate exposure inhibits eCB degradation in the developing brain to cause abnormal neurodevelopment? Aim 2. Will perinatal organophosphate treatment produce behavioral changes in adult animals? If so, are these changes mediated by CB1 signaling during development? Successful completion of these aims will enable us to determine if inhibition of eCB degradation and enhanced cannabinoid receptor signaling underlie the adverse neurodevelopmental effects of organophosphates. Furthermore they will help us understand the role of FAAH and MGL in orchestrating the complex task of assembling the nervous system. Finally, they will tell us if perturbation of MGL and FAAH function during development predisposes to later behavioral abnormalities and susceptibility to drug use. PUBLIC HEALTH RELEVANCE: Commonly used organophosphate pesticides can cause abnormalities in nervous system development. This proposal will test the hypothesis that organophosphate pesticides impair degradation of endogenous cannabinoids in the fetal and newborn brain and that this leads to anatomical and behavioral deficits in later life. The results of this study could have significant public health benefits for children exposed in utero to organophosphate pesticides.